In Part I & Part II we reviewed the
basic advantages of effective perioperative, multimodal pain control.
Analgesics coupled with sedative/tranquilizers provide a more comfortable
patient experience, reduce induction and maintenance agent requirements,
and generally improve patient morbidity and mortality. Multimodal
techniques reduce the dose of each individual drug which, in turn, reduces
the potential for adverse drug effects. Intervening before the pain system
becomes sensitized is an absolute necessity when your goal is optimal
patient benefit. In Part III, we will continue our review of the various
drug families and individual agents that may contribute to our
perioperative patient analgesic management.

SEDATIVE/TRANQUILIZERS represent an important element in any balanced analgesic strategy.
Unchecked, stress adds to the “inflammatory soup” that sensitizes the
nerve pathways[i] amplifying the patient’s pain. While not all of these drugs are direct
analgesics, they all enhance the patient’s total analgesic benefit[ii].

PHENOTHIAZINE
TRANQUILIZERS. ACEPROMAZINE, an alpha antagonist, is an
effective, inexpensive drug. Acepromazine is capable of reducing induction
and maintenance needs significantly. It possesses anti-arrhythmic and
antihistaminic qualities and reduces the incidence of preanesthetic
medication related vomiting[iii].
Potential adverse effects, including hypotension, are rarely seen with
proper patient selection and appropriate dosing. Hypothermia, from
peripheral vasodilation and hypothalamic influence, is best managed by
providing effective supplemental heat. The association between
acepromazine and seizures is a more tenuous connection than past
literature would suggest. In fact, acepromazine may reduce the frequency
of seizures in some dogs[iv],[v].
But we’ll leave that discussion for another day.

Acepromazine use as a sole agent is not
recommended. In general, acepromazine should always be used in combination
with an opioid. This combination provides significant analgesic and
sedative synergism. For dogs, doses from 0.005 to 0.050 are usually
effective when combined with 0.2 mg/kg butorphanol, 0.5 to 1.0 mg/kg
morphine, or 0.1 to 0.2 mg/kg hydromorphone. Cats appear somewhat less
responsive to the sedative effects of acepromazine making doses from 0.02
to 0.10 more appropriate when combined with 0.2 mg/kg butorphanol or 0.1
mg/kg hydromorphone. Buprenorphine, 0.020 to 0.060 mg/kg, can be
substituted for the above opioids but you will see less total sedation.

Lower doses of acepromazine are much more
easily managed by creating a vial of 1 mg/ml or 2 mg/ml concentration. To
create a 1 mg/ml final concentration, mix 9 ml sterile water with 1 ml
(10mg) acepromazine in a sterile vial. To create a 2 mg/ml final
concentration, mix 8 ml sterile water with 2 ml (20mg) acepromazine in a
sterile vial. Carefully label and date these vials. Dosing charts are
available for this and other drugs at www.vasg.org/support_material.htm.

Acepromazine may be repeated at small doses for
those patients experiencing emergence delirium or dysphoria at recovery
using 0.005 mg/kg increments. We will occasionally use low dose
medetomidine (0.0005 to 0.0010 mg/kg increments slowly IV) for postop
agitation in patients previously treated with acepromazine. On the surface
this might seem a conflict between alpha agonist and an alpha antagonist.
This appears more logical if one considers acepromazine’s alpha
antagonistic effects to be weighted towards the alpha-1 receptor while
medetomidine’s agonistic effects are quite selective for the alpha-2
receptor.

Acepromazine use should be avoided in
patients less than 12 weeks of age and those exhibiting significant liver
dysfunction, particularly those demonstrating elevated bilirubin,
hypoalbuminemia, and altered coagulation. Doses should be conservative, if
used at all, in the healthy geriatric patient.

This drug has been associated with some concern
regarding its use in Boxers. The main concern was based on strains found
in England but there are a few reported instances by anesthesiologists in
the US. The untoward effect is described as an acute bradycardic collapse
that does appear to be responsive to atropine and support.

ALPHA-2
AGONISTS. MEDETOMIDINE (Domitor®) is a very capable sedative
analgesic agent. The use of xylazine, a less selective alpha-2 agonist, is
not recommended by this author and will not be discussed. Medetomidine
benefits include stress reduction, dose related analgesia, muscle
relaxation, better maintenance of patient core body temperature, more
stable anesthetic planes, a general freedom from respiratory depression,
and, unlike xylazine, an anti-arrhythmic benefit[vi]. When medetomidine is included in the preanesthetic medications there is
a substantial reduction in patient induction and maintenance agent needs.
As with acepromazine, the potential for unwanted adverse effects is quite
low when medetomidine is used appropriately in combination with an opioid.
In contrast to acepromazine, medetomidine is a fully reversible agent
adding an extra element of flexibility.

Unfortunately, many have experienced
medetomidine as a sole agent used at label doses: doses that are as high
as 0.150 mg/kg (150 µg/kg). At these higher doses peripheral
vasoconstriction is pronounced, marked hypertension is common, and
bradycardia is often unsettling. Mucous membranes appear ashen, making it
difficult to obtain consistent pulse oximeters readings and indirect blood
pressures are hard to evaluate. In short, the author does not recommend
medetomidine use as a sole agent.

In a recent review presented by Dr. Grimm at
the 2004 ACVIM meeting, medetomidine and butorphanol were shown to be very
effective and safe when used in combination for heavy sedation to restrain
canine and feline patients for radiation therapy. The study reviewed 8191
sedation events in dogs averaging 8.9 years and cats averaging 10.8 year
of age. Each cat averaged 15 sedative events and each dog averaged 12
events. All patients were undergoing therapy for cancer management. There
were no fatalities during this sequence covering 8 years. Only 2.8% of the
patients required alterations in their protocol. Butorphanol was dosed at
0.22 mg/kg and the medetomidine was dosed, on average, at 0.0085 mg/kg for
the dogs and 0.017 mg/kg for the cats[vii].

Medetomidine is capable of providing
significant dose dependent analgesia. Analgesic duration is about 1 hour
at 0.010 mg/kg (10 µg/kg)[viii].
Medetomidine may be redosed every hour, slowly IV, to maintain its
analgesic and MAC sparing benefit.

Postanesthetic dysphoria and agitation usually
responds quite nicely to 0.001 to 0.002 mg/kg medetomidine slowly IV with
the residual sedation waning by 1 hour postadministration. Alternatively,
a constant rate infusion of 0.0005 to 0.001 mg/kg/hr medetomidine can be
of benefit in managing agitated patients over longer periods of time.

There appears to be significant analgesic and
sedative synergism between medetomidine and the opioids. As stated above,
when transitioning to medetomidine based protocols, you should anticipate
a significant reduction in the amount of induction agent and maintenance
agent needed. Dosing to effect is a necessity.

BENZODIAZEPINES include midazolam and diazepam. These tranquilizers are, as a
group, poorly effective as sole agents, especially in healthy energetic
pets. They are useful in combination with opioids, acepromazine and
medetomidine. Benzodiazepines are capable of providing muscle relaxation,
induction agent reduction and inhalant MAC reduction, and, possibly,
patient amnesia. The benzodiazepines are relatively free of unwanted side
effects. One often forgotten advantage of the benzodiazepines is their
reversibility; flumazenil (Romaziconâ)
is the benzodiazepine antagonist.

Midazolam (Versed®) is a
water-soluble agent while diazepam is only available in a propylene glycol
solution. As such, midazolam mixes well with most agents and it is rapidly
absorbed from the IM injection route while diazepam precipitates when
mixed with most agents (ketamine being the most important exception) and
it is more painful and less consistently absorbed when given IM. For all
practical purposes the two drugs have comparably dosing.

Benzodiazepines, 0.1 to 0.4 mg/kg, in
combination with a mu agonist often provide an effective preanesthetic
combination of analgesia and mild sedation for aged and depressed patients
as this combination has minimal impact on the patient’s cardiovascular
and respiratory function. This is not, however, an effective combination
for energetic, healthy patients. Acepromazine or medetomidine should be
added to the opioid/benzodiazepine base to more effectively manage younger
and healthier patients.

The only significant meaningful benefit from
the addition of midzaolam to the preanesthetic medications for an
energetic, healthy patient is the hoped for possibility that a certain
subgroup of the cat and dog population will experience periprocedural
amnesia as so often occurs in people given midazolam.

Midazolam and diazepam may be given at 0.2 to
0.4 mg/kg IV just prior to propofol administration to smooth the induction
process and significantly reduce the patient’s propofol requirement.
Expense considerations favor the use of diazepam for this application. The
addition of 0.5 mg/kg ketamine to the benzodiazepine further reduces
propofol need while reducing the likelihood of propofol induced
hypotension and apnea without creating any of the typical concerns
associated with higher dose ketamine use[ix].

Benzodiazepines are the preferred agents
delivered IV immediately prior to etomidate inductions. Etomidate is
considered to be the most attractive induction agent for patients with
cardiovascular instability, particularly those with serious myocardial
disease. Diazepam and midazolam given at 0.2 to 0.4 mg/kg IV prior to the
etomidate helps minimize the retching and muscle tremors that may
otherwise occur with that agent.

Benzodiazepines may also be used as an
intermittent bolus or as a constant rate infusion to help minimize
inhalant agent levels while maintain anesthetic depth for those patients
poorly tolerant of inhalant agents.

NMDA
ANTAGONISTS helps to prevent sensitization of the central
nervous system, reducing the exaggerated pain response that is otherwise a
potential development after any significant traumatic or surgical event[x].
NMDA antagonists enhance opioid analgesia and they help to combat the
opioid tolerance that may occur when opioids are given for long
periods of time.

KETAMINE is the most commonly utilized
veterinary NMDA antagonist. As the sole agent, at anesthetic doses, its
analgesic uses are limited. It is most effective when utilized at
subanesthetic doses as a constant rate infusion to antagonize the NMDA
receptors in the dorsal horn of the spinal cord. Given at typical
analgesic adjunct doses, ketamine is unlikely to affect cardiovascular,
CNS, or ophthalmologic concerns significantly, especially when
administered after an opioid to blunt potential sympathetic stimulation.
Constant rate analgesic infusions can be delivered prior to, during, and
after painful events. A more detailed discussion of CRIs will follow later
in this review series.

AMANTADINE is an antiviral drug that has also
demonstrated NMDA antagonistic properties. It is a useful addition to
long-term outpatient pain management when given at 3 to 5 mg/kg PO once
daily. It is available as a 100 mg capsule and a 10 mg/ml liquid.

NONSTEROIDAL
ANTI-INFLAMMATORY DRUGS have become a popular perioperative
pain management choice perhaps, in part, due to the fact that they are not
controlled by the DEA. NSAIDs act at both the peripheral level, where they
inhibit the inflammatory response, and the central nervous system level
combining to reduce both peripheral and centrally mediated sensitization
and hyperalgesia. There are many “new generation” NSAIDs. The
individual characteristics vary as to the variety of available
preparations, the frequency of administration, cost, and applicability to
cats versus dogs. NSAIDs have become increasing “selective” or
“preferential” in their ability to focus on the COX-2 and lipoxygenase
pathways. But, as has recently been shown on the human side of the
medicine fence, increasing selectivity is not without risks.

It is important to recognize that the COX-2
pathway has its beneficial (constitutive) qualities especially with
respect to the healing of GI injuries[xi] and in the maintenance of renal blood flow[xii],[xiii],[xiv],[xv].
It is this constitutive aspect of COX-2 oriented agents that raises
concerns regarding their preoperative use. Although there are studies
available that suggest a lack of adverse effects when NSAIDs are given
perioperatively to healthy dogs[xvi],[xvii],
it might seem prudent to limit their use to the postoperative period when
hypovolemia, hypotension, and GI surgical trauma has been fully assessed
and addressed. NSAID adverse affects on bone healing do not appear to be
overly concerning and certainly should not preempt short-term use in the
immediate postoperative orthopedic period.

There is a broad range of NSAIDs available for
use in dogs. There is no single NSAID that is considered the class leader,
as any given patient may respond and tolerate one better than another.
Therapeutic trials are the best determinant of NSAID choice for a given
patient. In general one should try to match a perioperative injectable
with subsequent oral medications as switching from one NSAID to another
has potential for adverse consequences, especially when moving from a less
selective agent to a more selective COX-2 agent. Carprofen (Rimadyl®),
etodolac (Etogesic®), deracoxib (Deramaxx®), tepoxalin (Zubrin®),
firocoxib (Previcox®), and meloxicam (Metacam®) are all approved for
canine use in the USA.

Conversely, there is only one approved NSAID
approved for use in cats in the USA; meloxicam injectable is the sole
NSAID, and sole form of meloxicam, approved for use in cats. There is
substantial support, though off-label, for the use of meloxicam 0.1 to 0.2
mg/kg
PO, SC on day one followed 24 hours later by 0.05 mg/kg PO SID
for up to 4 days. Support for long-term use beyond the initial 4 to 6 day
period exists with several different dosing plans offered:

0.05 mg/kg PO SID for 10 days followed by 0.025 mg/kg
PO SID
for an additional 10 days[xix]

Acute perioperative pain: 0.1 mg/kg to 0.2 mg/kg
(0.05 to 0.1 mg/lb) SC, PO followed by 0.05 mg/kg (0.025 mg/lb) for up
to 4 days if needed[xx]

Chronic pain:

0.1 mg/kg (0.05 mg/lb) SC, PO on day 1, followed
by 0.05 mg/kg (0.025 mg/lb) for up to 4 days, then reduce to lowest
effective dose ( 0.025
mg/kg PO once every 48 to 72 hours) if long term use is required (Lascelles
2007)[xx]

0.05 mg/kg (0.025 mg/lb) SC, PO on day 1,
followed by 0.025 mg/kg (0.0125 mg/lb) or less PO every 24 to 48 hours
(Robertson 2008)[xxi]

Long-term use must be applied very cautiously
with careful dosing accuracy and tight owner/patient monitoring as cats
have substantially longer NSAID half-lives than dogs creating significant
risks if excessive doses or dose frequency are used. All drops are not
created equally (just ask a drip set). Use a Tb or insulin syringe without
the needle for greatest oral liquid dosing accuracy.

NSAIDs alone may provide adequate analgesia for
only the most minor surgeries. For perioperative purposes, NSAIDs
effectiveness is enhanced significantly when they are preceded by, or
combined with, an opioid analgesic in conjunction with an effective
sedative/tranquilizer as outlines above (remember, butorphanol does not
count as a significant opioid analgesic). With appropriate preemptive
analgesia presurgically, NSAIDs may be adequate as a sole postoperative agent for mild to moderate surgical pain such as that associated with
spays and neuters in young healthy dogs and cats. NSAIDs should be teamed
with ongoing opioid analgesics (buprenorphine TM in cats, fentanyl patch,
tramadol) and, possibly, an NMDA antagonist like amantadine when managing
moderate to severe pain like that associated with declaws, mature spays,
orthopedics, thoracic surgery, and similar pain level procedures.

In summary, NSAIDs are most attractive when
used in a multimodal pain management strategy that includes an opioid and
an NMDA antagonist. NSAID use should be reserved for healthy patients free
of significant disease. Special cautions exist for patients that have
pre-existing renal or hepatic dysfunction, dehydration/hypovolemia/hypotension,
coagulopathies, ongoing corticosteroid therapy, GI disease, or pregnancy.
NSAIDs use should be limited to a single dose when used after cesarean
sections in nursing animals.

When used for more than a few days, patient
monitoring should include periodic hepatic and renal assessments to
include ALTs and urine specific gravities at a minimum. Testing is
preferred prior to use, at 2 weeks, 3 months, then every 3 to 6 months
thereafter depending on patient status and clinical history.